In 2010, the Office of the Inspector General estimated that up to 180,000 Americans die each year as a result of medical care, making harm due to medical care the 3rd leading cause of death nationwide. In addition, in November 2010, Landrigan et al. reported the results of a 10-center, 6-year study of harm due to medical care in the New England Journal of Medicine; the epidemic of harm in hospitals appeared unabated. Sleep deprivation and circadian misalignment resulting from resident physicians' recurrent extended work shifts may be an important contributor to this epidemic. Recently, a series of studies have found that residents in their first year after medical school (PGY1s) working recurrent shifts over 16 consecutive hours make more serious medical errors than do those working shorter shifts, and suffer more occupational injuries. After a year- long study that included a comprehensive review of the literature, the Institute of Medicine (IOM) concluded in 2009 that the scientific evidence base establishes that human performance begins to deteriorate after 16 hours of wakefulness, and called for the elimination of all resident-physician shifts without sleep exceeding 16 hours. In response, beginning in July 2011, the Accreditation Council for Graduate Medical Education (ACGME) will limit PGY1 residents to no more than 16 consecutive work hours. Second year (PGY2) and higher residents, however, will continue to work for up to 28 consecutive hours. In choosing not to more substantively limit the hours of PGY2 and higher residents - who represent 80% of all physicians-in-training - the ACGME indicated that insufficient data existed on these more senior trainees to take action. Through the Clinical and Translational Science Award (CTSA)-funded Sleep Research Network, the largest and only federally funded sleep science network in the U.S., we propose to conduct a multi-center randomized crossover trial in six pediatric ICUs to compare the safety of a sleep and circadian science-based (SCS) intervention schedule with a traditional schedule that includes frequent shifts of 24 or more hours. We will determine whether patient safety (as measured by rates of adverse events and near misses, collected using an intensive observational methodology), resident safety (as measured by the Optalert-based Johns Drowsiness Scale, a state-of-the-art real-time driving safety measure), resident sleep (measured by actigraphy and sleep logs) and resident neurobehavioral performance (measure by Psychomotor Vigilance Testing) is improved under the SCS schedule. In addition, we will gather genetic material for future testing of individual genetic susceptibility to the adverse effects of sleep deprivation and circadian misalignment, and will begin building and testing mathematical modeling tools to facilitate the implementation of optimized resident work schedules. This work will provide definitive data on the effectiveness of applying sleep and circadian science to residency scheduling, which, given the key role residents play in delivering care to the nation's sickest patients, could have major public health implications.